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Mechanisms compensating for dopamine loss in early Parkinson disease

From the Toronto Western Research Institute (J.B.), University Health Network, Toronto, Canada; and TEVA Pharmaceutical Industries Ltd. (C.F.-A.), Petach Tikva, Israel.

Address correspondence and reprint requests to Jonathan Brotchie, PhD, University Health Network, Toronto, Canada brotchie{at}uhnres.utoronto.ca

Parkinson disease (PD) is a disorder with a substantive period before the emergence of motor symptoms, during which significant dopaminergic neuronal loss is counterbalanced by endogenous compensatory mechanisms. Many potential compensatory mechanisms have now been proposed; these are both dopaminergic, focused on enhancing effects or exposure to existing dopamine, and nondopaminergic, being focused on reducing activity of the indirect striatal output pathway. Compensatory mechanisms can potentially postpone and reduce the severity of parkinsonian symptoms, and contribute to the benefit provided by a symptomatic therapy, thus offering targets for novel therapeutics. However, enhancement of certain compensatory mechanisms may produce problems when subsequent therapies are initiated, e.g., the development of motor complications with levodopa. Supporting endogenous compensatory mechanisms, to delay or reverse apparent disease progression, is a novel and attractive "disease-modifying" approach to PD. Such actions may contribute to the apparent disease-modifying benefit of initiating early treatment with levodopa or rasagiline, as suggested by the ELLDOPA and TEMPO studies.

Disclosure: The meeting at which this material was presented was supported by an unrestricted grant from Teva Pharmaceutical Industries Ltd. (Israel), Teva Neuroscience, Inc. (USA) and H. Lundbeck A/S (Denmark). Dr Fitzer-Attas is a current employee of Teva.